13-77896433-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001122659.3(EDNRB):c.*1767C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,554,920 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.013 (211 hom.)
• Consequence: EDNRB NM_001122659.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.225

Genes affected

EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

EDNRB-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-77896433-G-A is Benign according to our data. Variant chr13-77896433-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0144 (2197/152064) while in subpopulation EAS AF= 0.0259 (133/5138). AF 95% confidence interval is 0.0223. There are 44 homozygotes in gnomad4. There are 1181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.*1767C>T		3_prime_UTR_variant	7/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-11259G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.*1767C>T		3_prime_UTR_variant	7/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2197 AN: 151946 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00926

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0156 AC: 2636 AN: 169286 Hom.: 38 AF XY: 0.0158 AC XY: 1421 AN XY: 89872

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00498

Gnomad ASJ exome AF: 0.00975

Gnomad EAS exome AF: 0.0213

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0135 AC: 18876 AN: 1402856 Hom.: 211 Cov.: 31 AF XY: 0.0138 AC XY: 9584 AN XY: 692584

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0426

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0144 AC: 2197 AN: 152064 Hom.: 44 Cov.: 32 AF XY: 0.0159 AC XY: 1181 AN XY: 74322

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00925

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0130 Hom.: 19

Bravo AF: 0.00958

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

*9C>T in exon 7B of EDNRB: This variant is not expected to have clinical signifi cance because it has been identified in 1.2% (101/8104) of European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs3027092). -

Hirschsprung disease, susceptibility to, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.6
Dann	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3027092; hg19: chr13-78470568; COSMIC: COSV57527714; COSMIC: COSV57527714;